Methods of screening for vmat2 inhibitors

Abstract

The present application is related to methods of preparing pharmaceutical compositions comprising a VMAT2 inhibitor and/or identifying therapeutically effective dosages of a VMAT2 inhibitor, wherein the VMAT2 inhibitor is useful for treating neurological and psychiatric diseases and disorders and for achieving an occupancy rate between 80-96% in a subject.

What is claimed is: 
     
         1 . A method of preparing a pharmaceutical composition comprising a therapeutically effective dosage of a VMAT2 inhibitor, the method comprising:
 (a) administering an amount of a VMAT2 inhibitor to a subject;   (b) measuring in vivo VMAT2 occupancy of the VMAT2 inhibitor in the subject, wherein a VMAT2 occupancy rate between 80-96% is indicative of the amount of the VMAT2 inhibitor being a therapeutically effective dosage; and   (c) admixing the therapeutically effective dosage of the VMAT2 inhibitor with a pharmaceutically acceptable carrier.   
     
     
         2 . The method of  claim 1 , wherein VMAT2 occupancy is measured by one or more imaging techniques. 
     
     
         3 . The method of  claim 2 , wherein one or more imaging techniques comprise administering to the subject an imaging agent capable of binding VMAT2 and subsequently imaging the subject. 
     
     
         4 . The method of  claim 3 , wherein the imaging agent is a VMAT2 inhibitor. 
     
     
         5 . The method of  claim 1 or 2 , wherein VMAT2 occupancy is measured by a positron emission tomography (PET) assay. 
     
     
         6 . The method of  claim 5 , wherein the PET assay comprises administering to the subject a PET imaging agent capable of binding VMAT2 and subsequently imaging the subject. 
     
     
         7 . The method of  claim 5 or 6 , wherein the PET assay comprises:
 (a) administering to the subject a PET imaging agent capable of binding VMAT2;   (b) waiting a time sufficient for the PET imaging agent to bind VMAT2;   (c) imaging the subject one or more times;   (d) measuring the VMAT2 displacement of the PET imaging agent; and   (e) determining VMAT2 occupancy based on the measured VMAT2 displacement of the PET imaging agent.   
     
     
         8 . The method of  claim 7 , wherein the VMAT2 displacement of the PET imaging agent is measured at one or more time points during the imaging. 
     
     
         9 . The method of  claim 7 or 8 , further comprising imaging the subject prior to step (a) to obtain a baseline image. 
     
     
         10 . The method of any one of  claims 7 to 9 , wherein the VMAT2 inhibitor is administered to the subject after step (a). 
     
     
         11 . The method of any one of  claims 7 to 9 , wherein the VMAT2 inhibitor is administered to the subject after step (b). 
     
     
         12 . The method of any one of  claims 7 to 9 , wherein the VMAT2 inhibitor is administered to the subject after step (b) and prior to step (c). 
     
     
         13 . The method of any one of  claims 6 to 12 , wherein the PET imaging agent is a radiolabeled VMAT2 inhibitor. 
     
     
         14 . The method of any one of  claims 6 to 13 , wherein the PET imaging agent is a [ 11 C]-radiolabeled VMAT2 inhibitor. 
     
     
         15 . The method of any one of  claims 6 to 13 , wherein the PET imaging agent is a [ 18 F]-radiolabeled VMAT2 inhibitor. 
     
     
         16 . The method of any one of  claims 6 to 13 , wherein the PET imaging agent is a radiolabeled analog of a VMAT2 inhibitor selected from the group consisting of valbenazine, tetrabenazine, deutetrabenazine, dihydrotetrabenazine, NBI-750142, and AV-133. 
     
     
         17 . The method of any one of  claims 6 to 13 , wherein the PET imaging agent is a [ 11 C]- or [ 18 F]-radiolabeled analog of a VMAT2 inhibitor selected from the group consisting of valbenazine, tetrabenazine, deutetrabenazine, dihydrotetrabenazine, NBI-750142, and AV-133. 
     
     
         18 . The method of  claim 16 or 17 , wherein the radiolabeled analog of dihydrotetrabenazine is a radiolabeled analog of (+)-α-dihydrotetrabenazine. 
     
     
         19 . The method any one of  claims 6 to 18 , wherein the PET imaging agent is [ 18 F]-AV-133. 
     
     
         20 . The method of any one of  claims 1 to 19 , further comprising measuring the plasma concentration of the VMAT2 inhibitor in the subject. 
     
     
         21 . The method of  claim 20 , wherein the plasma concentration of the VMAT2 inhibitor is measured at one or more time points during the imaging of step (c). 
     
     
         22 . The method of  claim 20 , wherein the plasma concentration of the VMAT2 inhibitor is measured at one or more time points prior to the imaging of step (c). 
     
     
         23 . The method of  claim 20 , wherein the plasma concentration of the VMAT2 inhibitor is measured at one or more time points during the imaging of step (c) and prior to the imaging of step (c). 
     
     
         24 . The method of any one of  claims 20 to 23 , wherein the plasma concentration of the VMAT2 inhibitor is measured at one or more time points from about two hours prior to the imaging of step (c) until the end of the imaging. 
     
     
         25 . The method of any one of  claims 20 to 24 , wherein the plasma concentration of the VMAT2 inhibitor is measured at one or more time points from about one hour prior to the imaging of step (c) until the end of the imaging. 
     
     
         26 . The method of any one of  claims 1 to 25 , wherein the dose administered is identified as a therapeutically effective dosage if the VMAT2 occupancy is determined to be from at least 80% and no more than 95%. 
     
     
         27 . The method of any one of  claims 1 to 26 , further comprising monitoring the subject for one or more symptoms associated with a treatment-emergent adverse event (TEAE) after administration of the VMAT2 inhibitor. 
     
     
         28 . The method of  claim 27 , wherein the monitoring is performed for about 30 minutes to about 90 minutes after administration of the VMAT2 inhibitor. 
     
     
         29 . The method of  claim 27 , wherein the monitoring is performed for about 30 minutes to about 60 minutes after administration of the VMAT2 inhibitor. 
     
     
         30 . The method of any one of  claims 1 to 29 , further comprising identifying the subject as not exhibiting one or more symptoms associated with a TEAE after administration of the VMAT2 inhibitor. 
     
     
         31 . The method of any one of  claims 1 to 30 , further comprising identifying the subject as not exhibiting one or more symptoms selected from ptosis, decreased activity, sedation, anxiety, nausea, akathisia, and salivation after administration of the VMAT2 inhibitor. 
     
     
         32 . The method of any one of  claims 1 to 31 , wherein the subject has been identified as not exhibiting one or more symptoms associated with a TEAE after administration of the VMAT2 inhibitor. 
     
     
         33 . The method of any one of  claims 1 to 32 , wherein the subject has been identified as not exhibiting one or more symptoms selected from ptosis, decreased activity, and salivation after administration of the VMAT2 inhibitor. 
     
     
         34 . The method of any one of  claims 1 to 33 , wherein the dose administered is identified as a therapeutically effective dosage if VMAT2 occupancy is determined to be from at least 80% and no more than 95%. 
     
     
         35 . The method of any one of  claims 1 to 33 , wherein the dose administered is identified as a therapeutically effective dosage if VMAT2 occupancy is determined to be from at least 85% and no more than 95%. 
     
     
         36 . The method of  claim 35 , wherein the dose administered is identified as a therapeutically effective dosage if VMAT2 occupancy is determined to be from at least 85% and no more than 90%. 
     
     
         37 . A method of identifying a therapeutically effective dosage of a VMAT2 inhibitor, the method comprising:
 (a) administering an amount of a VMAT2 inhibitor to a subject;   (b) measuring in vivo VMAT2 occupancy of the VMAT2 inhibitor in the subject, and   (c) identifying a therapeutically effective dosage of a VMAT2 inhibitor when the VMAT2 occupancy rate of the amount of the VMAT2 inhibitor is between 80-96%.   
     
     
         38 . The method of  claim 37 , wherein VMAT2 occupancy is measured by one or more imaging techniques. 
     
     
         39 . The method of  claim 38 , wherein one or more imaging techniques comprise administering to the subject an imaging agent capable of binding VMAT2 and subsequently imaging the subject. 
     
     
         40 . The method of  claim 39 , wherein the imaging agent is a VMAT2 inhibitor. 
     
     
         41 . The method of  claim 37 or 38 , wherein VMAT2 occupancy is measured by a positron emission tomography (PET) assay. 
     
     
         42 . The method of  claim 41 , wherein the PET assay comprises administering to the subject a PET imaging agent capable of binding VMAT2 and subsequently imaging the subject. 
     
     
         43 . The method of  claim 41 or 42 , wherein the PET assay comprises:
 (a) administering to the subject a PET imaging agent capable of binding VMAT2;   (b) waiting a time sufficient for the PET imaging agent to bind VMAT2;   (c) imaging the subject one or more times;   (d) measuring the VMAT2 displacement of the PET imaging agent; and   (e) determining VMAT2 occupancy based on the measured VMAT2 displacement of the PET imaging agent.   
     
     
         44 . The method of  claim 43 , wherein the VMAT2 displacement of the PET imaging agent is measured at one or more time points during the imaging. 
     
     
         45 . The method of  claim 43 or 44 , further comprising imaging the subject prior to step (a) to obtain a baseline image. 
     
     
         46 . The method of any one of  claims 43 to 45 , wherein the VMAT2 inhibitor is administered to the subject after step (a). 
     
     
         47 . The method of any one of  claims 43 to 45 , wherein the VMAT2 inhibitor is administered to the subject after step (b). 
     
     
         48 . The method of any one of  claims 43 to 45 , wherein the VMAT2 inhibitor is administered to the subject after step (b) and prior to step (c). 
     
     
         49 . The method of any one of  claims 42 to 48 , wherein the PET imaging agent is a radiolabeled VMAT2 inhibitor. 
     
     
         50 . The method of any one of  claims 42 to 49 , wherein the PET imaging agent is a [ 11 C]-radiolabeled VMAT2 inhibitor. 
     
     
         51 . The method of any one of  claims 42 to 49 , wherein the PET imaging agent is a [ 18 F]-radiolabeled VMAT2 inhibitor. 
     
     
         52 . The method of any one of  claims 42 to 49 , wherein the PET imaging agent is a radiolabeled analog of a VMAT2 inhibitor selected from the group consisting of valbenazine, tetrabenazine, deutetrabenazine, dihydrotetrabenazine, NBI-750142, and AV-133. 
     
     
         53 . The method of any one of  claims 42 to 49 , wherein the PET imaging agent is a [ 11 C]- or [ 18 F]-radiolabeled analog of a VMAT2 inhibitor selected from the group consisting of valbenazine, tetrabenazine, deutetrabenazine, dihydrotetrabenazine, NBI-750142, and AV-133. 
     
     
         54 . The method of  claim 52 or 53 , wherein the radiolabeled analog of dihydrotetrabenazine is a radiolabeled analog of (+)-α-dihydrotetrabenazine. 
     
     
         55 . The method any one of  claims 42 to 54 , wherein the PET imaging agent is [ 18 F]-AV-133. 
     
     
         56 . The method of any one of  claims 37 to 55 , further comprising measuring the plasma concentration of the VMAT2 inhibitor in the subject. 
     
     
         57 . The method of  claim 56 , wherein the plasma concentration of the VMAT2 inhibitor is measured at one or more time points during the imaging of step (c). 
     
     
         58 . The method of  claim 56 , wherein the plasma concentration of the VMAT2 inhibitor is measured at one or more time points prior to the imaging of step (c). 
     
     
         59 . The method of  claim 56 , wherein the plasma concentration of the VMAT2 inhibitor is measured at one or more time points during the imaging of step (c) and prior to the imaging of step (c). 
     
     
         60 . The method of any one of  claims 56 to 59 , wherein the plasma concentration of the VMAT2 inhibitor is measured at one or more time points from about two hours prior to the imaging of step (c) until the end of the imaging. 
     
     
         61 . The method of any one of  claims 56 to 60 , wherein the plasma concentration of the VMAT2 inhibitor is measured at one or more time points from about one hour prior to the imaging of step (c) until the end of the imaging. 
     
     
         62 . The method of any one of  claims 37 to 61 , wherein the dose administered is identified as a therapeutically effective dosage if the VMAT2 occupancy is determined to be from at least 80% and no more than 95%. 
     
     
         63 . The method of any one of  claims 37 to 62 , further comprising monitoring the subject for one or more symptoms associated with a treatment-emergent adverse event (TEAE) after administration of the VMAT2 inhibitor. 
     
     
         64 . The method of  claim 63 , wherein the monitoring is performed for about 30 minutes to about 90 minutes after administration of the VMAT2 inhibitor. 
     
     
         65 . The method of  claim 63 , wherein the monitoring is performed for about 30 minutes to about 60 minutes after administration of the VMAT2 inhibitor. 
     
     
         66 . The method of any one of  claims 37 to 65 , further comprising identifying the subject as not exhibiting one or more symptoms associated with a TEAE after administration of the VMAT2 inhibitor. 
     
     
         67 . The method of any one of  claims 37 to 66 , further comprising identifying the subject as not exhibiting one or more symptoms selected from ptosis, decreased activity, sedation, anxiety, nausea, akathisia, and salivation after administration of the VMAT2 inhibitor. 
     
     
         68 . The method of any one of  claims 37 to 67 , wherein the subject has been identified as not exhibiting one or more symptoms associated with a TEAE after administration of the VMAT2 inhibitor. 
     
     
         69 . The method of any one of  claims 37 to 68 , wherein the subject has been identified as not exhibiting one or more symptoms selected from ptosis, decreased activity, and salivation after administration of the VMAT2 inhibitor. 
     
     
         70 . The method of any one of  claims 37 to 69 , wherein the dose administered is identified as a therapeutically effective dosage if VMAT2 occupancy is determined to be from at least 80% and no more than 90%. 
     
     
         71 . The method of claim any one of  claims 37 to 69 , wherein the dose administered is identified as a therapeutically effective dosage if VMAT2 occupancy is determined to be from at least 85% and no more than 95%. 
     
     
         72 . The method of  claim 71 , wherein the dose administered is identified as a therapeutically effective dosage if VMAT2 occupancy is determined to be from at least 85% and no more than 90%. 
     
     
         73 . The method of any one of  claims 1-72 , further comprising measuring synaptic dopamine in the subject by
 (iii) administering radioligand [ 11 C](+)4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol ([ 11 C]-PHNO) to the subject; and   (iv) image scanning the subject;   wherein a 20-45% increase in ([ 11 C]-PHNO binding potential relative to the non-displaceable binding ([ 11 C]-PHNO BP ND ) corresponds to a decrease in synaptic dopamine and is indicative of the amount of the VMAT2 inhibitor being a therapeutically effective dosage.   
     
     
         74 . A method of preparing a pharmaceutical composition comprising a therapeutically effective dosage of a VMAT2 inhibitor, the method comprising:
 admixing the therapeutically effective dosage of the VMAT2 inhibitor with a pharmaceutically acceptable carrier;   wherein the therapeutically effective dosage of the VMAT2 inhibitor was identified by   measuring in vivo VMAT2 occupancy of the VMAT2 inhibitor in a subject previously administered with an amount of the VMAT2 inhibitor, wherein a VMAT2 occupancy rate between 80-96% was indicative of the amount of the VMAT2 inhibitor being a therapeutically effective dosage.   
     
     
         75 . The method of  claim 74 , further comprising measuring synaptic dopamine in a subject previously administered with an amount of the VMAT2 inhibitor by
 (i) administering radioligand [ 11 C](+)4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol ([ 11 C]-PHNO) to the subject; and   (ii) image scanning the subject;   wherein a 20-45% increase in ([ 11 C]-PHNO binding potential relative to the non-displaceable binding ([ 11 C]-PHNO BP ND ) corresponded to a decrease in synaptic dopamine and was indicative of the amount of the VMAT2 inhibitor being a therapeutically effective dosage.